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Study Description

TAPISTRY is a Phase II, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in rational, specified combinations in participants with unresectable, locally advanced or metastatic solid tumors determined to harbor specific oncogenic genomic alterations or who are tumor mutational burden (TMB)-high as identified by a validated next-generation sequencing (NGS) assay.

Participants with solid tumors will be treated with a drug or drug regimen tailored to their NGS assay results at screening.

Participants will be assigned to the appropriate cohort based on their genetic alteration(s). Treatment will be assigned on the basis of relevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and, unless otherwise specified, will continue until disease progression, loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first.

Cohort A: ROS1 fusion-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 milligram per day (mg/day) for pediatric participants with a body surface area (BSA) >/= 1.51 m²

Cohort B: Cohort B: NTRK1/2/3 fusion-positive tumors - Open

Participants with metastatic or advanced solid tumors will receive entrectinib once daily in repeated 28-day cycles at a dose of 600 mg/day for adults and pediatric participants with a BSA >/= 1.51 m²

Cohort C: ALK fusion-positive tumors (excluding NSCLC) - Closed to Accrual

Participants with metastatic or advanced solid tumors, with the exception of NSCLC, will receive alectinib at a dosage of 600 mg orally twice a day (BID), taken with food, in repeated 28-day cycles.

Cohort D: TMB-high tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive atezolizumab intravenously (IV) at a dose of 15 mg/kg (maximum 1200 mg) for participants aged < 18 years on Day 1 of each 21-day cycle.

Cohort E: AKT1/2/3 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive ipatasertib orally once daily (QD). For participants 12-17 years of age, ipatasertib will be administered at the starting dose of 200 mg for participants <35 kg, 300 mg for participants >/= 35 and <45 kg, 400 mg for those >/=45 kg orally QD in repeated 28-day cycles until the participant experiences disease progression, intolerable toxicity, or withdraws consent.

Cohort F: HER2 mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive trastuzumab emtansine IV at a dose of 3.6 mg/kg every 21 days. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort H: PIK3CA multiple mutant-positive tumors - Closed to Accrual

Participants with metastatic or advanced solid tumors will receive GDC-0077 daily at a starting dose of 9 mg by mouth (PO) in repeated 28-day cycles. This dosage and administration method also applies for pediatric participants 12-17 years of age.

Cohort I: BRAF class II mutant or fusion-positive tumors - Closed to Accrual

Participants with BRAF class II mutant/fusion-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort J: BRAF class III mutant-positive tumors - Closed to Accrual

Participants with BRAF class III mutant-positive tumors (adults and adolescents ≥ 40 kg) will receive 400 mg belvarafenib by mouth (PO) BID (twice a day) with adequate water (more than 200 mL). One cycle consists of 28 days. Administration of belvarafenib should occur BID on every day of each 28-day cycle.

Cohort K: RET fusion-positive tumors - Closed to Accrual

Participants with RET fusion-positive tumors will self-administer Pralsetinib orally at home (except on clinic days) on a continuous daily dosing regimen at a dose of 400 mg/day (four 100-mg capsules per day) for adult and pediatric patients ≥ 12 and < 18 years of age. A treatment cycle consists of 4 weeks (28 days).

Inclusion Criteria

• In addition to the general inclusion criteria below, participants must meet all of the cohort-specific inclusion criteria for the respective cohort
• Briefly - for arm A, a ROS1 fusion is required; for arm B, a NTRK1/2/3 fusion is required; for arm D, a TMB >16mut/Mb is required; for arm E: specific mutations in the AKT gene are required; for arm F: specific mutations in the HER2 gene are required; for arm H, specific mutations in the PIK3CA gene are required; for arm I, a BRAF Class II mutation or fusion is required; for arm J, a BRAF Class III mutation is required; for Cohort K; a RET fusion is required. 
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participants aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria

Exclusion Criteria

• Current participation or enrollment in another therapeutic clinical trial
• Any anticancer treatment within 2 weeks or 5 half-lives prior to start of study treatment
• Whole brain radiotherapy within 14 days prior to start of study treatment
• Stereotactic radiosurgery within 7 days prior to start of study treatment
• Pregnant or breastfeeding, or intending to become pregnant during the study
• History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study or confounds the ability to interpret data from the study
• Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina
• History of another active cancer within 5 years prior to screening that may interfere with the determination of safety or efficacy of study treatment with respect to the qualifying solid tumor malignancy
• In addition to the general exclusion criteria above, in order to be enrolled in a treatment cohort of the study, participants must not meet any of the cohort-specific exclusion criteria

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.

The study will be conducted in two sequential phases:

Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later.

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Phase A (Feasibility Phase) - Open at SickKids

A feasibility phase will be conducted to establish the maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using the Rolling 6 design.

Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination with vinblastine (4mg/m2) will be used as the starting dose and will be de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Phase B (Expansion/Efficacy Phase) - Not Yet Open

Once the MTD/RP2D of the combination, vinblastine + tovorafenib has been established, the expansion/efficacy phase will be initiated at the dose determined in Phase A.

Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Inclusion Criteria

• Patients must be less than or equal to 25 years of age at the time of enrollment
• Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.
• Diagnosis:
  • All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
  • Patient must have progressive or recurrent LGG.
  • Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.
  • Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.
• Prior Therapy:
  • Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.
  • Patients must have fully recovered from the acute toxic effects (≤ Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.
    • i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.
    • iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.
    • iv. Patients must have recovered from acute effects of any prior surgery. 
    • v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2, except ongoing retinopathy which must be ≤ Grade 1.
• Performance Level: a) Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Tumor Tissue Sample Confirmation that an archival tumor tissue sample is available. If an archival tumor tissue sample is not available, a fresh biopsy should be performed at baseline. Submission of tumor tissue and a blood sample are mandatory and must be submitted within 14 days from enrollment onto the study and prior to initiation of treatment. Biopsy may be either at initial diagnosis or recurrence.
• Organ function: 
  • Adequate bone marrow function defined as:
    • i. Absolute neutrophil count ≥ 1000/mm3
    • ii. Platelet count (unsupported) ≥ 100 x 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to enrollment)
    • iii. Hemoglobin (unsupported)≥ 10.0 g/dL (transfusions allowed per institutional guidelines; last transfusion > 4 weeks prior to enrollment)
    • iv. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor.
  • Adequate hepatic and renal function defined as:
    • i. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (patients with documented Gilbert's disease may be enrolled with sponsor approval and total bilirubin ≤ 2 x ULN)
    • ii. Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • iii. Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST) ≤ 2.5 x ULN
    • iv. Serum creatinine within normal limits or estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 based on local institutional practice for determination.
  • Thyroid functions tests within institutional normal range. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting therapy are eligible.
  • Adequate cardiac function defined as:
    • i. Left ventricular ejection fraction (LVEF) of ≥ 50% as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional shortening (FS) ≥ 25% (Tissot et al., 2018) as measured by ECHO, within 14 days before enrollment (while not receiving medications for cardiac function). If normal practice at the institution is to provide the LVEF result as a range of values, then the upper value of the range will be used to determine the result.
    • ii. QTc (by Fridericia's formula) < 470ms as measured by electrocardiogram (ECG) within 14 days before enrollment (while not receiving medications for cardiac function).
  • Adequate central nervous system (CNS) function defined as:
    • i. Patients with seizures should be stable and not have experienced a significant increase in seizure frequency within 14 days prior to enrollment.
    • ii. Patients with neurologic deficits should have deficits that are stable for a minimum of 14 days prior to enrollment.
    • iii. Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose, no increase or decrease) for 14 days prior to enrollment.
• Study specific:
  • Baseline ophthalmology assessment within 28 days of study enrollment.
  • MRI assessment within 28 days of study enrollment. MRI done for clinical indication but within the window for study would be permitted as baseline.
  • Ability to comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
  • Willingness of male and female patients with reproductive potential to use double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Effective birth control methods are described in Appendix H.
  • Ability to swallow tablets or liquid, or gastric access via a nasal or gastric tube.
  • Patient is able to start treatment within 14 working days of screening.
  • Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study ICF and applicable pediatric assent form before initiation of any protocol related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.

Exclusion Criteria

• Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
• Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
• History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
• Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study.
• Major surgery within 14 days (2 weeks) prior to enrollment (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval > 470 ms based on triplicate ECG average.
• Concomitant medications that are strong inhibitors or inducers of CYP2C8 or CYP3A4 within 14 days before initiation of therapy. Concomitant medications that are substrates of BCRP with a narrow therapeutic index within 14 days before initiation of therapy
• Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed.
• Active systemic bacterial, viral, or fungal infection.
• Nausea and vomiting ≥ National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2 (for those not controlled by supportive care), malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
• Patient has CTCAE v5.0 Grade 3, creatine phosphokinase (CPK) elevation (> 5 × ULN - 10 × ULN).
• Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures).
• Pregnancy or lactation.
• History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS). Patients with hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product.
• Other unspecified reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a multicenter pilot study of SurVaxM (SVN53-67/M57-KLH) for children and young adults with progressive or relapsed medulloblastoma, high grade glioma, ependymoma and newly diagnosed diffuse intrinsic pontine glioma.

Survivin (BIRC5) is an inhibitor of apoptosis (IAP) protein that is highly expressed in many cancers. Survivin's high level of expression in certain pediatric malignancies makes it an attractive molecular target for new therapies, including active specific vaccination-based immunotherapy.

The design of the SurVaxM vaccine employs several strategies to create an effective antitumor immunogen, including: 1) incorporation of multiple MHC class I epitopes, 2) peptide modification to enhance binding to certain MHC class I molecules, 3) cytokine helper support, and 4) antibody-mediated tumor cell killing. All of these effects would not be expected with the unmodified class-I restricted short survivin peptides employed in previously studied glioma vaccines.

There are no prior clinical trials of SurVaxM in pediatric patients; however, SurVaxM has been studied in several adult trials, including a phase I study conducted at Roswell Park Comprehensive Cancer Center. Following the single-institution phase I trial, a multicenter phase IIa trial (NCT024455557) was conducted in 63 patients with newly diagnosed glioblastoma. All patients in this study underwent surgical resection of their tumors. Patients then underwent chemoradiation with temozolomide according to the Stupp protocol. This was followed by a one-month hiatus from chemotherapy, during which priming doses of SurVaxM were initiated. The priming phase of vaccination was then followed by initiation of standard adjuvant chemotherapy with temozolomide and maintenance doses of SurVaxM as an add-on to standard chemotherapy. There have been no regimen-limiting toxicities (RLT) or grade ≥ 3 SAE attributable to SurVaxM, with most toxicities being related to temozolomide. The most common AE was grade 1-2 injection site reaction with 2 patients experiencing Montanide-related granulomatous panniculitis with local skin ulceration at vaccine injection sites, both of which resolved. Humoral and survivin-specific CD8+ T cell responses were observed in almost all patients. Twelve-month overall survival (OS12) was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Although not a randomized trial, these results are superior to overall survival reported in various studies in which patients received standard of care treatment for this disease. A randomized phase IIb clinical trial of standard therapy plus SurVaxM is currently being developed with intent for drug registration, if successful.

The primary objective of this trial is to assess the toxicity profile of SurVaxM in emulsion with Montanide plus sargramostim in children with relapsed or progressive medulloblastoma and high-grade glioma, ependymoma and non-recurrent diffuse intrinsic pontine glioma post-radiation therapy. Patients will be enrolled into three separate strata based on age and diagnosis. Enrollment will be staged to allow for safety evaluations between strata.

Each patient will receive 500 micrograms SurVaxM as a 1:1 mixture with Montanide ISA 51 in a water-in-oil emulsion. The SurVaxM-Montanide emulsion injection will be followed immediately by sargramostim (or biosimilar) given via a second separate subcutaneous injection in close proximity to the vaccine injection site. Patients will receive four injections administered over a 6-week period, followed by 14 days of follow-up, called the Priming Phase (8 weeks total). Beginning 8 weeks after the fourth priming dose, a maintenance dose of SurVaxM with Montanide ISA 51 may be given every 8 weeks (± 2 weeks) for two years or until an off-treatment criterion is met.

Inclusion Criteria

• DIAGNOSIS: Patients with a histologically confirmed diagnosis of a primary CNS tumor that is progressive or recurrent defined as progression in any known residual tumor, or the appearance of one or more new lesions, or new cerebrospinal fluid (CSF) positivity for malignant cells, after having failed standard therapy. At the time of diagnosis or recurrence, all tumors must have histologic verification of one of the following:
  • Medulloblastoma
  • Glioblastoma multiforme (GBM)
  • Anaplastic astrocytoma
  • High-grade astrocytoma, NOS
  • Anaplastic oligodendroglioma
  • Anaplastic ependymoma (WHO Grade III)
  • Ependymoma (WHO Grade II)
  • Diffuse Intrinsic Pontine Gliomas (DIPG) Patients:
    • Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 14 to 56 days post-completion of radiation therapy if they do not have any evidence of progression. Patients with diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation. Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and are proven to be a glioblastoma multiforme (GBM), or astrocytoma (Grade II or Grade III). DIPG patients with disseminated disease are not eligible, and MRI of spine must be performed if disseminated disease is suspected by the treating physician.
• DEMONSTRATION OF SURVIVIN EXPRESSION: For patients with relapsed or progressive medulloblastoma, HGG, or ependymoma, demonstration of survivin expression as assessed after screening consent/assent of at least 1% on tumor tissue by immunohistochemistry (ICH) is required and must have been performed in the central laboratory at Roswell Park Comprehensive Cancer Center (RPCCC) to confirm eligibility. For patients with DIPG, diagnostic biopsy for histologic confirmation is not required, and tumor expression of survivin is therefore not required for eligibility for these patients.
• DISEASE STATUS: Patients must have either measurable or evaluable disease. Patients with recurrent or progressive GBM, anaplastic astrocytoma, high grade astrocytoma (NOS), anaplastic oligodendroglioma, anaplastic ependymoma (WHO Grade III) or ependymoma (WHO Grade II) with metastatic disease or leptomeningeal disease are eligible so long as there is clear MRI evidence of evaluable disease.
• AGE: 
  • Stratum 1 (progressive or recurrent) patients must be ≥10 years of age and ≤ 21 years of age at the time of study screening.
  • Stratum 2 (progressive or recurrent) patients must be ≥1 year of age and < 10 years of age at the time of study screening.
  • Stratum 3 (newly diagnosed DIPG) patients must be ≥1 year of age and ≤ 21 years of age at the time of study enrollment
• PRIOR THERAPY: 
  • Patients with recurrent or progressive disease must have received prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality.
  • Patients must have recovered from the acute treatment related toxicities (defined as ≤ Grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
  • Patients with newly diagnosed DIPG must have completed radiation therapy
• CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment.
• INVESTIGATIONAL/ BIOLOGIC AGENT:
  • Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment.
  • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
• RADIATION:
  • Recurrent or Progressive CNS tumor patients must have had their last fraction of:
  • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
  • Focal irradiation ≥ 14 days prior to enrollment.
  • DIPG Patients: Patients with DIPG are eligible after completion of initial radiotherapy (with or without concurrent treatment) and in the absence of progressive disease.
  • Patients must have completed radiation therapy at least 14 days prior to enrollment but no longer than 56 days and cannot have received any other tumor-directed treatment except the following: Patient may have received temozolomide or other non-investigational agents during irradiation at the treating physician's discretion. If the patient has received such agents concurrently with radiation, then patient must have recovered from the acute treatment related toxicities (defined as < Grade 1) prior to enrollment.
• CELLULAR THERAPY: Patient must be:
  • ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease.
  • ≥ 3 months since autologous stem cell transplant prior to enrollment.
  • > 42 days since completion of any other type of adoptive cellular therapy prior to enrollment.
• CRANIAL SURGERY: Patients who have had recent cranial surgery (VP shunt, ETV, tumor resection) are eligible for inclusion, but the vaccine may not be administered prior to post-operative Day 14.
• NEUROLOGIC STATUS: Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study.
• PERFORMANCE STATUS: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 2 weeks prior to enrollment must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below:
  • Absolute neutrophil count ≥ 0.75 x 109 cells/L
  • Platelets ≥ 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
  • Hemoglobin ≥ 8 g/dl (may receive transfusions)
  • PT/INR, PTT ≤ 1.5 x ULN
  • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)
  • ALT(SGPT) ≤ 3 x institutional upper limit of normal
  • Albumin ≥ 2 g/dl
  • Blood creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for age/gender:
  • Age 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female)
  • Age 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
  • Age 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
  • Age 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
  • Age 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
  • Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• INFECTIOUS DISEASES
  • Human Immunodeficiency Virus (HIV) Infected Individuals: Patients who are known to be Human immunodeficiency virus (HIV)-infected must be on effective anti-retroviral therapy with undetectable viral load for 6 months prior to study enrollment.
  • Hepatitis B Chronically Infected Individuals: For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Hepatitis C (HCV) Infected Individuals: Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with known HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• CORTICOSTEROIDS: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. A maximum dose of 0.1 mg/kg/day (and maximum total daily dose 4 mg) of dexamethasone (or equivalent) is permitted at study entry. Effort should be made to reduce to lowest tolerated steroid dose. Patients must be willing to use brief courses (at least 72 hours) of steroids as directed for potential inflammatory side effects of the therapy if recommended by their treating physician.
• GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at least 14 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). Two (2) weeks must have elapsed if the patient received a long-acting formulation.
• PREGNANCY - Pregnant women or nursing mothers are excluded from this study because SurVaxM is an agent with the potential for teratogenic effects. Female patients of childbearing potential must have a negative serum or urine pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
• INFORMED CONSENT - The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

• BREAST FEEDING WOMEN - Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SurVaxM breastfeeding should be discontinued if the mother is treated with SurVaxM. Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed.
• CONCURRENT ILLNESS:
  • Active, uncontrolled infection requiring treatment (including HIV infection)
  • Patients with spinal cord primary tumors
  • Patients with relapsed or progressive DIPG or midline glioma
  • Patients with Grade I myxopapillary ependymoma
  • Patients with WHO Grade I or II gliomas are not eligible unless tumor is located within the pons or brainstem
  • Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, with the exception of:
  • Patients with vitiligo or resolved asthma/atopy
  • Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
  • History of or ongoing pneumonitis or significant interstitial lung disease
  • Patients with any clinically significant unrelated systemic illness (significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
  • Any medical condition that, in the opinion of the Principal Investigator, would compromise the patient's ability to participate in the study.
• CONCOMITANT MEDICATIONS:
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
  • Patients who are receiving any cannabidiol (CBD) or medical marijuana treatment are ineligible.
  • Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
  • Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14 days of the start of protocol therapy are ineligible.
  • Patients may not be on immunosuppressive therapy, including corticosteroids (except as defined in the corticosteroids inclusion criteria) at time of enrollment. However, patients who require intermittent use of bronchodilators, local steroid injections, or topical steroids will not be excluded from the study.
  • Patients may not be receiving concomitant chemotherapy, immunotherapy, radiotherapy, radiosurgery, interferon, allergy desensitization injections, growth factors, interleukins, or any investigational therapeutic medication at the time of enrollment.
• INABILITY TO PARTICIPATE: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity of therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
• ALLERGY: Known allergy or hypersensitivity to Keyhole Limpet Hemocyanin (KLH), granulocyte colony-macrophage stimulating factor (sargramostim) or MRI contrast agent.
• BLEEDING DISORDER: Patients with a known coagulopathy or bleeding diathesis or requires the use of systemic, anticoagulant medication are not eligible.
• BULKY DISEASE: Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as any of the following:
  • Tumor with evidence of clinically significant uncal herniation causing midbrain compression or midline shift greater than 5 mm
  • Tumor with a diameter >4cm in one dimension on T2/FLAIR
  • Tumor that in the opinion of the site investigator, shows significantly rapid progression of mass effect in either the brain or spinal cord such that the priming phase of vaccination (i.e., 6 weeks) cannot be completed before clinical deterioration is likely to occur.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This phase I trial studies the side effects and best dose of volitinib in treating patients with primary central nervous system (CNS) tumors that have come back (recurrent) or does not respond to treatment (refractory). Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib (savolitinib) administered orally daily in children with refractory, progressive or recurrent primary CNS tumors.

II. To define and describe the toxicities of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

III. To characterize the pharmacokinetics of savolitinib in children with refractory, progressive, or recurrent primary CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of savolitinib within the confines of a phase I study.

II. To perform a genomic analysis within the confines of a phase I study to investigate correlation between response to treatment (as measured by objective response or progression free survival [PFS]) and the presence of specific genomic alterations (e.g. MET amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific subgroups of disease.

OUTLINE: This is a dose-escalation study.

Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years.

Inclusion Criteria

• Patients with a histologically confirmed diagnosis of a primary CNS tumor (medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that is recurrent, refractory, or progressive. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with diffuse intrinsic brain stem tumors. These patients must have radiographic or clinical evidence of progression. Patients with a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology, are also eligible to the Phase I component of this study
  • Note: Refractory disease is defined as the presence of persistent abnormality on conventional magnetic resonance imaging (MRI) imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment
• Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory primary CNS tumor with evidence of genetic activation of the MET pathway, regardless of histology. The submitted specimen can be from diagnosis or recurrence and there is no time limit from when the specimen was obtained to enrollment onto the efficacy expansion cohort. The assessment will be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory. MET pathway activation status must be confirmed using Food and Drug Administration (FDA) approved testing prior to enrollment. MET pathway activation is defined as:
  • MET kinase domain mutations, allelic frequency >= 5% OR
  • MET or HGF amplification, >= 6 copies OR
  • Chromosome 7 gain OR
  • MET fusion
    • If a MET aberration is identified using local testing at a Pediatric Brain Tumor Consortium (PBTC) institution, final confirmation for eligibility to the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) panel. Alternatively, if a MET aberration is identified at a PBTC site using another FDA approved panel (Foundation Medicine or Oncomine), the result will be considered sufficient for eligibility following study chair review
• Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available for the required correlative studies. If target amounts of tissue or number of slides are not available, the site must obtain study chair/co-chair approval for adequacy of submitted tumor samples and prioritization of studies to be performed, prior to patient enrollment
  • Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
• Patients must have evaluable disease to be eligible. Evaluable disease is defined as the presence of at least one lesion that can be measured accurately in at least 2 (two) dimensions
• Patients must be > 5 years and =< 21 years of age at the time of study enrollment
• Body surface area (BSA)
  • Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
  • Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
  • Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67 m^2
  • Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2 and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the dose finding phase only)
• Patients must have failed prior standard therapy for their tumor. Patients with medulloblastoma must have received radiation therapy in addition to platinum and alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have at least received radiation therapy. Patients must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if it included nitrosourea
• Biologic or investigational agent (anti-neoplastic):
  • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
    • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Monoclonal antibody treatment and agents with known prolonged half-lives:
    • Patients must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
• Patients must have had their last fraction of:
  • Craniospinal irradiation or total body irradiation or radiation to >= 50% of pelvis > 3 months prior to enrollment
  • Focal irradiation > 4 weeks prior to enrollment
• Patients must be:
  • >= 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
  • >= 3 months since autologous stem cell transplant prior to enrollment
• Both males and females of all races and ethnic groups are eligible for this study
• Neurologic Status
  • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
  • Patients with seizure disorders may be enrolled if seizures are well controlled
  • Patients must be able to swallow whole tablets to be eligible for study enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
  • Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell transfusions are not allowed within 14 days prior to enrollment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5 x ULN with ALT and AST =< 1 x ULN
• Albumin >= 2 g/dL
• Serum creatinine based on age/gender. Patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
  • Age: Maximum serum creatinine (mg/dL)
  • 2 to < 6 years: 0.8 (male and female)
  • 6 to < 10 years: 1 (male and female)
  • 10 to < 13 years: 1.2 (male and female)
  • 13 to < 16 years: 1.5 (male), 1.4 (female)
  • >= 16 years: 1.7 (male), 1.4 (female)
• International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters
• Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for >= 2 weeks
• Cardiac function:
  • Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3 electrocardiograms (EKGs)
• Oxygen saturation as measured by pulse oximetry is > 93% on room air
• Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment
• Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
• Pregnancy Prevention
  • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
  • Women of child-bearing potential should use effective contraception from the time of enrollment until 4 weeks after discontinuing study treatment
  • Male study participants should use a condom with female partners of child-bearing potential during the study and for 4 weeks after discontinuing study treatment
  • If the female partner of a male study participant is not using effective contraception, men must use a condom during the study and for 6 months after discontinuing study treatment
  • Male study participants should avoid fathering a child and refrain from sperm donation from study start to 6 months after discontinuing study treatment
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Other inclusion criteria may apply and will be discussed with you by the study team.

Exclusion Criteria

• Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because there are unknown but potential risks to an unborn baby from savolitinib. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with savolitinib, breastfeeding should be discontinued if the mother is treated with savolitinib
• Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis
• Patients with any clinically significant unrelated systemic illness or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile for age, height, and gender, patients with values above these levels must have their blood pressure controlled with medication prior to starting study drug)
  • The normal blood pressure by height, age and gender tables can be assessed in the Generic Forms section of the PBTC member's webpage
• Patients with any of the following cardiac diseases
  • Congestive heart failure (New York Heart Association >= grade 2)
  • Clinically significant cardiac arrhythmia
  • Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3 electrocardiograms (EKGs) or
  • Factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or
  • Family history of unexplained sudden death under 40 years of age in first-degree relatives or
  • Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. These drugs must have been discontinued prior to the start of administration of study treatment in accordance with guidance
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting EKG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
• Concurrent Therapy
  • Patients who are receiving any other anticancer or investigational drug therapy
  • Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates should not be used during the trial or used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. Patient drug information handout and wallet card should be provided to patients
  • Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib, cabozantinib, or onartuzumab)
• Patient is currently receiving any of the following herbal preparations or medications and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's wort). These herbal medications include, but are not limited to: cannabis products, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• Patient has undergone major surgical procedure =< 28 days prior to beginning study drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting is required following port-a-cath placement
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study

Other exclusion criteria may apply and will be discussed with you by the study team.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

This is a Phase I study to evaluate the safety profile of a type of immune therapy called HER2 CAR T cells (short for HER2 chimeric antigen receptor T cells). In addition to looking for side effects, we will study how well this treatment works against a brain tumor called ependymoma that has come back after treatment (recurrent) or has not responded well to treatment (progressive) in children. The HER2 CAR T cells used in this trial are made from the patient's own blood. A new gene, called the HER2 CAR, will be inserted into patient's T cells to allow them recognize a protein on the tumor called HER2. These HER2-specific CAR T cells may be able to target and kill ependymoma tumors that express HER2. This research is also studying how doable it is to provide this type of CAR T cell treatment to children being treated at different hospitals.

The primary objectives of the Phase I study are to determine the safety of intravenous injection of HER2-specific CAR T cells after lymphodepleting chemotherapy, and to evaluate the multicenter feasibility of administering up to three infusions of HER2-CAR T cells after lymphodepletion.

Patients will receive one infusion of HER2psecific CAR T cells after lymphodepleting chemotherapy. Following recovery from their first treatment (no earlier than 8 weeks and no later than 12 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions after lymphodepleting chemotherapy if they meet laboratory parameters. The length of time on study for patients enrolled on the Phase I study is anticipated to be 9 months on treatment. Patients will then be followed for 15 years after treatment.

Surgical Study

The objective of the Surgical study is to evaluate the post-treatment tumor tissue for presence of HER2-specific CAR T cells administered intravenously in children undergoing surgical resection. The surgical study will be initiated following completion of the safety evaluation period of 6 patients treated in the Phase I study.

Once the surgical study is open for enrollment, all patients who have clinical indication for surgery, except those needing urgent surgery, will be eligible for enrollment to the surgical study. Patients will receive one infusion of HER2-specific CAR T cells after lymphodepleting chemotherapy 4-6 weeks before surgical resection of their tumor, at which time samples will be taken for analysis. Following recovery from surgery (no earlier than 8 weeks and no later than 15 weeks), patients will resume treatment with HER2-specific CAR T cells for up to 2 infusions if they meet laboratory parameters.

The first patient in the surgical study will complete a 6-week safety evaluation period prior to enrollment of the subsequent patient. The length of time on study for patients enrolled on the Surgical study is anticipated to be 10 months on treatment. Patients will then be followed for 15 years after treatment.

Dosing

All patients on Phase I and Surgical study will receive HER2 CAR T cells at a patient-specific dose level 1 (8x10^7 CAR-positive T cells/m^2) for infusion. The cell dose will be based on the patient weight and height obtained by the treating institution at the time of procurement. For patients whose BMI is greater than 95th percentile for given age and sex, the Body surface area (BSA) will be calculated using the ideal body weight.

In the event that dose level 1 is found to have excessive toxicity, three additional doses of CAR T cells at dose level -1 (5x10^7 CAR-positive T cells/m^2) will be made to be used in the event that dose de-escalation occurs before a patient is enrolled for treatment.

Inclusion Criteria

Inclusion Criteria - Treatment

1. Diagnosis: Patients with a histologically confirmed diagnosis of HER2 positive ependymoma that is recurrent or progressive. Histologic verification may be from time of diagnosis or time of recurrence. In cases where there is question of recurrence, histologic verification, or verification of progression on follow up imaging is required prior to enrolling for protocol treatment.
2. Disease Status: 
   • Phase I (Stratum 1) - Patients must have evaluable disease to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows:
     • Measurable disease (enhancing or non-enhancing tumor):
       • at least 1 cm, or
       • at least two times (in both perpendicular diameters) the MRI slice thickness, plus the interslice gap.
     • Non-measurable disease (tumor that is too small to be accurately measured):
       • less than 1 cm in at least one perpendicular dimension, or
       • less than two times the MRI slice thickness, plus the interslice gap.
     • Note: Leptomeningeal disease is considered non-measurable but evaluable.
     • Surgical Study (Stratum 2) - Patients with measurable disease (Section 3.3.1.2.1) in whom tumor resection is clinically indicated and feasible after the CAR T cell infusion.
3. Age: Patient must be ≥ 1 but ≤ 22 years of age at the time of enrollment for treatment.
4. HER2 CAR T cell product: The patient must have, at a minimum, one prescribed dose of the cryopreserved, autologous HER2 CAR T cell product available for infusion.
5. Prior Anti-neoplastic Therapy:
   • Cytotoxic chemotherapy: Patients must not have received cytotoxic chemotherapy for at least 28 days prior to study enrollment for treatment and must have recovered from the acute treatment related toxicities (defined as < grade 1 if not defined in eligibility criteria; excludes alopecia) prior to entering this study.
   • Biological, targeted, or investigational agents (anti-neoplastic): Patients must have a period of at least 28 days from the last receipt of said drug and must have recovered from all acute toxic effects.
     • For agents that have known acute adverse events occurring beyond 28 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
   • Monoclonal antibodies, checkpoint inhibitors, and other agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
   • Adoptive cellular therapies: Patient must have recovered from any acute toxicity potentially related to the cellular product and received their last dose of the cellular product at least 90 days prior to study enrollment. (Note: Patients who have previously received an adoptive cellular therapy may continue long-term follow up evaluations per the prior study's evaluation schedule as needed for assessment of long-term toxicities including genotoxicity.)
   • Radiation: Patients must have had their last fraction of:
     • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >50% of pelvis or spine ≥ 3 months prior to enrollment (90 days) prior to enrollment.
     • Focal palliative irradiation to the tumor ≥ 42 days prior to enrollment. c. Patients who receive tumor-directed radiation (non-palliative) should have confirmed disease progression on the imaging study done at least 6 weeks after the completion of the last fraction of radiation.
   • Surgery: Patients must have not had surgery within 14 days of enrollment for treatment and must have adequate wound healing and recovered from other acute effects from surgery. One exception is the placement of central venous catheter which will be allowed at any time point until treatment initiation on the study.
6. Growth Factors: Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). 14 days must have elapsed if the patient received a long-acting formulation.
7. Corticosteroids: Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least 14 days prior to enrollment for treatment, and corticosteroid dose must be less than or equal to dexamethasone 0.5 mg/m2/day (or equivalent) during the 14 days preceding enrollment. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
8. Neurologic Status: In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment for treatment on the study. Patients with seizure disorders may be enrolled if seizures are well controlled.
9. Performance Status: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week of enrollment must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
10. Organ Function: Patients must have adequate organ and bone marrow function as defined in Section 3.2.1.4.
11. Pregnancy Prevention: Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
12. Informed Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
    • Patients who meet eligibility criteria per Section 3.3.1.2.1 must be enrolled using Phase I treatment consent (Stratum 1).
    • Patients who meet eligibility criteria per Section 3.3.1.2.2 must be enrolled using Surgical Study treatment consent (Stratum 2).

Please note there is additional criteria for screening, outlined below: 

1. Tumor: Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.

2. Prior Therapy: Patient must have received standard of care therapy including maximal safe surgical resection followed by local adjuvant radiation therapy prior to enrollment.

3. Adequate Pre-trial Tumor Tissue: Patient must have adequate pre-trial tumor material available to determine HER2 status. Tumor tissue from the most recent resection or biopsy of recurrent disease in preferred. If unavailable, tumor tissue from prior recurrences or from the time of initial diagnosis is acceptable.

   a. One exception will be patients who have previously received HER2-directed therapy (including but not limited to trastuzumab); these patients will need evaluation of tumor HER2 status after stopping treatment due to the possibility of HER2 downregulation or loss. Tumor biopsy will not be performed for the purpose of HER2 screening. Patients will not be eligible for screening on PBTC-059 if tumor tissue is not available or inadequate for HER2 testing. Tumor screening by Immunohistochemistry (IHC) will be done centrally using the testing method validated at Texas Children's Hospital. Sample for screening must be shipped within 7 days of enrollment for screening.

4. Known HIV Positivity: Patients that are known to be HIV-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.

5. Age: Patient must be ≥ 1 but ≤ 21 years of age at the time of screening consent.

6. Screening Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.

7. Potential Eligibility for Study Treatment Enrollment: Patients are screened for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 if their tumor is HER2-positive.

Please note there is additional criteria for procurement, outlined below: 

Criteria for Procurement: All subjects must meet following inclusion and exclusion eligibility criteria at the time of peripheral blood procurement for manufacturing the HER2 CAR T-cell product. No exceptions will be given. All clinical and laboratory evaluations to establish eligibility for procurement must be done within 14 days prior to enrollment. See Section 6.1 for details of laboratory requirements and planning of procurement blood collection date.

1. Tumor: Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
2. Performance Score: Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week of procurement must be ≥ 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score provided the neurological deficit is stable as described in Section 3.3.1.7.
3. Prior Therapy: Patients must have received last dose of cytotoxic chemotherapy greater than 21 days preceding the date of enrollment for procurement.
4. Organ Function: Patient must have adequate organ and bone marrow function as defined below:
   • Peripheral absolute neutrophil count (ANC) > 1.0 x 109 cells/L
   • Platelet count ≥ 75 100 x 109 cells/L (unsupported, defined as no platelet transfusion within 4 days)
   • Hemoglobin ≥ 8 g/dL (may receive red blood cell transfusions)
   • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
   • Alanine transaminase (ALT /SGPT) and Aspartate aminotransferase (AST/SGOT) ≤ 3 x institutional upper limit of normal (ULN) for age
   • Serum creatinine < 1.5 x institutional upper limit of normal for age and gender. Patients that do not meet the criteria but have a 24-hour Creatinine Clearance or Glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
   • Pulmonary Function
     • Oxygen saturation as measured by pulse oximetry is ≥ 93% on room air
5. Concomitant Medication: Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least two weeks prior to procurement, and corticosteroid dose must be less than or equal to dexamethasone 0.75 mg/m2/day (or equivalent). Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
6. Procurement Consent: The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
7. Potential Eligibility for Study Enrollment: Patients whose blood samples have been successfully procured for this trial should be reasonably anticipated to meet the criteria for treatment described in Section 3.3 and to begin treatment within 180 days from the date of procurement. The treatment slot will not be held beyond the specified 180 days, and such patients may not be able to receive treatment on this study depending on slot availability.

Exclusion Criteria

Exclusion Criteria: Treatment

1. Patients with Bulky Tumors on Imaging Studies
   • Bulky tumors will be defined as those:
     • > 6 cm in single maximum dimension, or
     • tumor causing uncal herniation or mass effect leading to midline shift with or without symptoms or signs of impending herniation or
     • obstruction to Cerebrospinal fluid (CSF) flow.
2. Infratentorial tumors with symptoms or signs arising from brain stem involvement by the tumor. Patients with stable cranial nerve deficit(s) secondary to prior surgery will not be excluded.
3. Surgical Study (Stratum 2): Patients who have urgent need for surgical resection of tumor.
4. Pregnancy or Breast-feeding
   • Pregnant women or nursing mothers are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of start of enrollment for treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant or breast-feeding women are excluded from this study because there is an unknown but potential risk of adverse events to the fetus or the nursing infant with the use of T cells genetically modified to express HER2 CAR. Pre-clinical studies in mice demonstrate the target antigen HER2 is necessary for normal fetal development of cardiac trabeculae, cranial sensory ganglia, and motor neuron development.75 Additionally, the lymphodepleting chemotherapy drugs fludarabine and cyclophosphamide are both Pregnancy Class D drugs.
5. Concurrent Illness: 
   • Patients with active autoimmune disease, documented history of autoimmune disease/syndrome, or any other condition that requires ongoing systemic steroids or systemic immunosuppressive agents, except a. Patients with vitiligo or resolved asthma/atopy b. Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome c. Patients requiring physiologic doses of corticosteroids (up to 0.5 mg/m2/day dexamethasone equivalent)
   • History of or ongoing pneumonitis or significant interstitial lung disease
   • Ongoing or active uncontrolled infection
   • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator, would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
   • Patients with any of the following cardiac diseases
     • New York Heart Association (NYHA) functional class III or IV
     • Clinically significant cardiac arrhythmia including, but not limited to, Torsade de pointes or requiring a pacemaker
     • Left ventricular ejection fraction below 50% as determined by echocardiography (ECHO)
   • Known HIV positivity
     • HIV-positive patients are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
6. Concomitant Medications:
   • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
   • Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible.
     • Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and must meet timeline for live vaccine.
   • Herbal preparations/medications (except for vitamins) including, but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment.
7. Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
8. Allergy: Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition (murine protein-containing products, Dimethylsulfoxide (DMSO), or dextran 40).

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Study Description

NOTE: Enrollment for DIPG and DMG has been discontinued. This study is only opened for patients with HGG without a H3 K27M mutation. 

This phase I/II trial tests the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy in treating children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic change called H3 K27M mutation.

It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. Glioma is a type of cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when it is growing and spreading quickly. The term, risk, refers to the chance of the cancer coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the brainstem that controls functions like breathing, swallowing, speaking, and eye movements). This trial has two parts. The only difference in treatment between the two parts is that some subjects treated in Part 1 may receive a different dose of selinexor than the subjects treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to determine the dose of selinexor that can be given without causing side effects that are too severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against HGG or DIPG.

Selinexor blocks a protein called CRM1, which may help keep cancer cells from growing and may kill them. It is a type of small molecule inhibitor called selective inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.

CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor orally (PO) on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a magnetic resonance imaging (MRI) and may undergo a biopsy during screening.

MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.

FOLLOW UP: After completion of study treatment, patients are followed every 3 months for year 1 (i.e., 3, 6, 9, 12 months), then every 6 months for years 2-3 (i.e., 18, 24, 30, 36 months), and finally once yearly for years 4-5 of this study.

Inclusion Criteria

PRE-ENROLLMENT

• Patients must be =< 25 years of age at the time of enrollment on APEC14B1 part A central nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening
  • Please note:
    • This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.
    • Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are >= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
  • Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)
• For patients with non-pontine tumors:
  • Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A. 
  • The specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery
• For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821

MAIN ENROLLMENT

• Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• Patients must have newly-diagnosed DIPG or HGG (including DMG).
• Stratum DIPG: - NOW CLOSED 
  • Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.
  • Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS], and/or H3 K27M-mutant) by institutional diagnosis.
• Stratum DMG (with H3 K27M mutation) - NOW CLOSED
  • Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
  • Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.
• Stratum HGG (without H3 K27M mutation) - OPEN
  • Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
  • Please note: 
    • Patients who fall in this category and who are >= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available
    • Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =<16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Meet clinical criteria as follows:
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)
  • Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
  • Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) OR
    • A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):
      • Age / Maximum Serum Creatinine (mg/dL):
        • 1 to < 2 years / male: 0.6; female: 0.6
        • 2 to < 6 years / male: 0.8; female: 0.8
        • 6 to < 10 years / male: 1; female: 1
        • 10 to < 13 years / male: 1.2; female: 1.2
        • 13 to < 16 years / male: 1.5; female: 1.4
        • >= 16 years / male: 1.7; female: 1.4
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
  • Serum amylase =< 1.5 x ULN
  • Serum lipase =< 1.5 x ULN
  • No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0).
  • For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.
• All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria

• Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
• Patients who are currently receiving another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents are not eligible.
• Patients >=18 years of age who have H3 K27M-wild type HGG.
• Patients who have an uncontrolled infection.
• Patients who have received a prior solid organ transplantation.
• Patients with grade > 1 extrapyramidal movement disorder.
• Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.
• Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
• Patients who are not able to receive protocol specified radiation therapy.
• Female patients:
  • Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants. It is not known whether selinexor is excreted in human milk.
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.

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Study Description

Brief Summary:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Detailed Description:

Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

• Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
• Arm 3: Subjects who are relapsed or refractory with active disease.

Inclusion Criteria

• All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
• All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
• Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.

• Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
  4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
  5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
  6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

  7. Stem Cell Transplant:

     1. Allogeneic: No evidence of active graft vs. host disease
     2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
  8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
• Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
• Life expectancy > 2 months
• All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.

• Subjects must have adequate organ functions at the time of registration:

  • Hematological: Total absolute neutrophil count ANC ≥750/μL
  • Liver: Subjects must have adequate liver function as defined by AST and ALT <5x upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
  • Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria

• BSA of <0.25 m2.
• Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
• Subjects that received a dose of DFMO in combination with etoposide are not eligible.
• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from hematological and bone marrow suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

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Study Description

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB using a 3+3 design for subjects with newly diagnosed DIPG or DMG following completion of radiation therapy. Given this is a first in-human study of rHSC-DIPGVax, an initial study "Lead In" will assess the tolerability of vaccine monotherapy first in older children (ages 5 to 18 years of age) followed by younger children (12 months to 18 years of age).

Sequential Parts A and B of this study will also first enroll patients ages 5 to 18 years of age before enrolling younger children. The rationale for the combination of vaccine and anti-PD1 therapy includes evidence of a more profound intra-tumoral response with addition of inhibition of negative co-regulatory pathways, such as, PD1/PDL1 and the need to overcome potentially immunosuppressive or immune "cold" microenvironment of gliomas. Anti-CLTA4 therapy will also be combined with rHSC-DIPGVax in the dose escalation portion of this study because of the ability of anti-CTLA4 therapy to induce T cell priming to promote T memory formation. Given the lack of standard treatment options for DIPG and DMG patients, this clinical trial will use combinatorial immunotherapy in upfront treatment of these patients in hopes of maximizing potential efficacy in this at-risk population while still assessing safety throughout.

Part A will evaluate rHSC-DIPGVax plus BALSTILIMAB. Pharmacokinetics (PK) of BALSTILIMAB will also be evaluated to assess exposure. If the rHSC-DIPGVax plus BALSTILIMAB is well tolerated in Part A for 28-days, this study will then move to enrolling Part B to evaluate the safety and tolerability of rHSC-DIPGVax and BALSTILIMAB in combination with ZALIFRELIMAB at two dose levels for a total therapy duration of one year or twenty-seven cycles, whichever occurs first.

Advancement from Part A to Part B and dose escalation in Part B will follow a conservative 3+3 design. The dose limiting toxicity (DLT) monitoring period will last 28 days (2 cycles) for Part A subjects and 42 days (1 cycle) for Part B. Subjects will be allowed to continue on in Part A for twenty-seven 14-day cycles or nine 42-day cycles in Part B or 1 year of total therapy, whichever comes first.

After the RP2D of ZALIFRELIMAB is determined, Part C, the expansion arm, will enroll further subjects at this dose level to assess futility versus efficacy. All subjects in trial Part C will be monitored for dose limiting toxicities for the duration of their participation in the study to monitor for excess toxicity.

Inclusion Criteria

• Subjects with newly diagnosed typical or non-typical, biopsy-proven DIPG or DMG are eligible for study enrollment. Biopsy is not required for subjects with radiographically typical DIPG meeting imaging criteria. Biopsy is required for DMG's and non-radiographically typical DIPG. Histone mutation must be confirmed by pathology report. Radiographically typical DIPG defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons.
• Subjects ages > or = to 12 months and < or = 18 years ("Lead In", Part A, and Part B require first three patients be > or = to 12 years of age)
• BSA > or = 0.35m2 at the time of study enrollment
• Performance score: Karnofsky >50% of subjects >16 years of age and Lansky > or = 50 for subjects < or = 16 years of age. Subjects who are unable to walk because of paralysis but are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.
• Must start radiation therapy within 42 days from date of diagnostic imaging. C1D1 must be within 42 days to 70 days post radiation (6-10 weeks). Patients CANNOT receive temozolomide during radiation
• Corticosteroids should be weaned as tolerated after radiation therapy with the goal of < or = 0.5mg/kg/day for a minimum of 7 days prior to enrollment.
• Subjects must have measurable disease

Exclusion Criteria

• Patients cannot receive temozolomide during radiation
• Disseminated disease
• Subjects who have received any cancer therapy except for radiation
• Autoimmune or immune disorders
• Active respiratory disorder or infection
• Active viral infection